chr12-95980836-C-G

Variant names:

• chr12-95980836-C-G
• rs7297245
• NM_002108.4:c.1315G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002108.4(HAL):​c.1315G>C​(p.Val439Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V439I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAL NM_002108.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 42 publications found

Genes affected

HAL (HGNC:4806): (histidine ammonia-lyase) Histidine ammonia-lyase is a cytosolic enzyme catalyzing the first reaction in histidine catabolism, the nonoxidative deamination of L-histidine to trans-urocanic acid. Histidine ammonia-lyase defects cause histidinemia which is characterized by increased histidine and histamine and decreased urocanic acid in body fluids. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

HAL Gene-Disease associations (from GenCC):

• histidinemia

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23042151).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002108.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	NM_002108.4	MANE Select	c.1315G>C	p.Val439Leu	missense	Exon 16 of 21	NP_002099.1
	HAL	NM_001258334.2		c.1315G>C	p.Val439Leu	missense	Exon 16 of 20	NP_001245263.1
	HAL	NM_001258333.2		c.691G>C	p.Val231Leu	missense	Exon 15 of 20	NP_001245262.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAL	ENST00000261208.8	TSL:1 MANE Select	c.1315G>C	p.Val439Leu	missense	Exon 16 of 21	ENSP00000261208.3
	HAL	ENST00000546999.5	TSL:1	n.*744G>C		non_coding_transcript_exon	Exon 15 of 20	ENSP00000447675.1
	HAL	ENST00000546999.5	TSL:1	n.*744G>C		3_prime_UTR	Exon 15 of 20	ENSP00000447675.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.050	N
PhyloP100		2.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.18
Sift	Benign	0.069	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.55		Gain of catalytic residue at N443 (P = 0)
MVP		0.37
MPC		0.14
ClinPred		0.76	D
GERP RS		4.8
PromoterAI		-0.013	Neutral
Varity_R		0.13
gMVP		0.52
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7297245; hg19: chr12-96374614;